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1.
Impaired Cholesterol-Uptake Capacity of HDL Might Promote Target-Lesion Revascularization by Inducing Neoatherosclerosis After Stent Implantation.
Nagano, Y, Otake, H, Toba, T, Kuroda, K, Shinkura, Y, Tahara, N, Tsukiyama, Y, Yanaka, K, Yamamoto, H, Nagasawa, A, et al
Journal of the American Heart Association. 2019;(9):e011975
Abstract
Background We evaluated the importance of high-density lipoprotein (HDL) functionality for target-lesion revascularization in patients treated with coronary stents using a rapid cell-free assay system to evaluate the functional capacity of HDL to accept additional cholesterol (cholesterol-uptake capacity; CUC). Methods and Results From an optical coherence tomography (OCT) registry of patients treated with coronary stents, 207 patients were enrolled and their HDL was functionally evaluated by measuring the CUC. Follow-up OCT was performed (median duration, 24.5 months after stenting) to evaluate the presence of neoatherosclerosis. Clinical follow-up was performed to assess target-lesion revascularization for a median duration of 42.3 months after stent implantation. Neoatherosclerosis was identified in 37 patients (17.9%). Multivariate logistic regression analysis revealed that a decreased CUC was independently associated with neoatherosclerosis (odds ratio, 0.799; P<0.001). The CUC showed a significant inverse correlation with incidence of target-lesion revascularization (odds ratio, 0.887; P=0.003) and with lipid accumulation inside stents, suggesting that neoatherosclerosis contributes to the association between CUC and target-lesion revascularization. Conclusions Impaired HDL functionality, detected as decreased CUC, might lead to future stent failure by provoking atherogenic changes of the neointima within stents. Both quantitative and qualitative assessments of HDL might enable the improved prediction of clinical outcomes after stent implantation.
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2.
Different Patterns of HIV-1 Replication in MACROPHAGES is Led by Co-Receptor Usage.
Borrajo, A, Ranazzi, A, Pollicita, M, Bellocchi, MC, Salpini, R, Mauro, MV, Ceccherini-Silberstein, F, Perno, CF, Svicher, V, Aquaro, S
Medicina (Kaunas, Lithuania). 2019;(6)
Abstract
Background and objectives: To enter the target cell, HIV-1 binds not only CD4 but also a co-receptor β-chemokine receptor 5 (CCR5) or α chemokine receptor 4 (CXCR4). Limited information is available on the impact of co-receptor usage on HIV-1 replication in monocyte-derived macrophages (MDM) and on the homeostasis of this important cellular reservoir. Materials and Methods: Replication (measured by p24 production) of the CCR5-tropic 81A strain increased up to 10 days post-infection and then reached a plateau. Conversely, the replication of the CXCR4-tropic NL4.3 strain (after an initial increase up to day 7) underwent a drastic decrease becoming almost undetectable after 10 days post-infection. The ability of CCR5-tropic and CXCR4-tropic strains to induce cell death in MDM was then evaluated. While for CCR5-tropic 81A the rate of apoptosis in MDM was comparable to uninfected MDM, the infection of CXCR4-tropic NL4.3 in MDM was associated with a rate of 14.3% of apoptotic cells at day 6 reaching a peak of 43.5% at day 10 post-infection. Results: This suggests that the decrease in CXCR4-tropic strain replication in MDM can be due to their ability to induce cell death in MDM. The increase in apoptosis was paralleled with a 2-fold increase in the phosphorylated form of p38 compared to WT. Furthermore, microarray analysis showed modulation of proapoptotic and cancer-related genes induced by CXCR4-tropic strains starting from 24 h after infection, whereas CCR5 viruses modulated the expression of genes not correlated with apoptotic-pathways. Conclusions: In conclusion, CXCR4-tropic strains can induce a remarkable depletion of MDM. Conversely, MDM can represent an important cellular reservoir for CCR5-tropic strains supporting the role of CCR5-usage in HIV-1 pathogenesis and as a pharmacological target to contribute to an HIV-1 cure.
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3.
Survival of an epidemic MDR strain of Mycobacterium tuberculosis and its non-prosperous variant within activated macrophages.
Yokobori, N, Monteserin, J, Rearte, B, Paul, R, Símboli, N, López, B, Ritacco, V, Sasiain, MDC
Infection, genetics and evolution : journal of molecular epidemiology and evolutionary genetics in infectious diseases. 2019;:248-254
Abstract
The fitness of a pathogen results from the interaction of multiple factors favoring either epidemiological success or failure. Herein, we studied the performance of the M strain, a highly successful multidrug resistant Mycobacterium tuberculosis genotype, and its non-prosperous variant, the 410 strain, in activated human monocyte-derived macrophages. Both strains showed comparable ability to induce necrotic cell death and to survive in apoptotic macrophages. Of the various macrophage activation conditions tested, none led to an enhanced control of the outbreak strain. The combination of 1,25(OH)2 vitaminD3 and IFN-γ favored significantly the control of the non-prosperous 410 strain. These observations indicate that the ability of the M strain to survive within the hostile intracellular milieu is conserved, and the overall fitness cost paid by this genotype would be low. Our results provide additional evidence on bacterial traits that may have contributed to the epidemiological success of the M strain.
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4.
[The immunomodulatory role of sodium].
Agócs, RI, Sugár, D, Pap, D, Szabó, AJ
Orvosi hetilap. 2019;(17):646-653
Abstract
High salt intake, which is common in the Western world, is the cause of several lifestyle diseases. Recent investigations shed light on novel extrarenal processes, which play role in the maintenance of sodium balance. In the short term, sodium storage of the skin may serve as a buffer against volume overload arising from the osmotic properties of sodium. Increased tissue sodium concentration may also potentiate immune response against infections. In the long run, however, tissue sodium concentration over a certain limit may initiate pathophysiological processes by provoking inflammatory response. Due to the immune modulating role of sodium, the effector cells of the innate as well as the adaptive immune system are activated, while certain regulator cells of the same systems are repressed, ultimately resulting in a proinflammatory state characterized by the imbalance of the immune system. Experiments applying dietary salt overload/salt depletion imply the role of sodium in the initiation/exacerbation of several diseases. Thus the relationship between sodium and the immune system may give an explanation to the pathomechanism of diseases with so far unknown origin such as hypertonia (primary, salt sensitive) or autoimmune diseases - all these putting tremendous pressure on the healthcare system due to their increasing incidence. Orv Hetil. 2019; 160(17): 646-653.
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5.
Subclinical atherosclerosis and its progression are modulated by PLIN2 through a feed-forward loop between LXR and autophagy.
Saliba-Gustafsson, P, Pedrelli, M, Gertow, K, Werngren, O, Janas, V, Pourteymour, S, Baldassarre, D, Tremoli, E, Veglia, F, Rauramaa, R, et al
Journal of internal medicine. 2019;(6):660-675
Abstract
BACKGROUND Hyperlipidaemia is a major risk factor for cardiovascular disease, and atherosclerosis is the underlying cause of both myocardial infarction and stroke. We have previously shown that the Pro251 variant of perilipin-2 reduces plasma triglycerides and may therefore be beneficial to reduce atherosclerosis development. OBJECTIVE We sought to delineate putative beneficial effects of the Pro251 variant of perlipin-2 on subclinical atherosclerosis and the mechanism by which it acts. METHODS A pan-European cohort of high-risk individuals where carotid intima-media thickness has been assessed was adopted. Human primary monocyte-derived macrophages were prepared from whole blood from individuals recruited by perilipin-2 genotype or from buffy coats from the Karolinska University hospital blood central. RESULTS The Pro251 variant of perilipin-2 is associated with decreased intima-media thickness at baseline and over 30 months of follow-up. Using human primary monocyte-derived macrophages from carriers of the beneficial Pro251 variant, we show that this variant increases autophagy activity, cholesterol efflux and a controlled inflammatory response. Through extensive mechanistic studies, we demonstrate that increase in autophagy activity is accompanied with an increase in liver-X-receptor (LXR) activity and that LXR and autophagy reciprocally activate each other in a feed-forward loop, regulated by CYP27A1 and 27OH-cholesterol. CONCLUSIONS For the first time, we show that perilipin-2 affects susceptibility to human atherosclerosis through activation of autophagy and stimulation of cholesterol efflux. We demonstrate that perilipin-2 modulates levels of the LXR ligand 27OH-cholesterol and initiates a feed-forward loop where LXR and autophagy reciprocally activate each other; the mechanism by which perilipin-2 exerts its beneficial effects on subclinical atherosclerosis.
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6.
Microcalcifications Drive Breast Cancer Occurrence and Development by Macrophage-Mediated Epithelial to Mesenchymal Transition.
Scimeca, M, Bonfiglio, R, Menichini, E, Albonici, L, Urbano, N, De Caro, MT, Mauriello, A, Schillaci, O, Gambacurta, A, Bonanno, E
International journal of molecular sciences. 2019;(22)
Abstract
BACKGROUND This study aims to investigate: (a) the putative association between the presence of microcalcifications and the expression of both epithelial-to-mesenchymal transition and bone biomarkers, (b) the role of microcalcifications in the breast osteoblast-like cells (BOLCs) formation, and (c) the association between microcalcification composition and breast cancer progression. METHODS We collected 174 biopsies on which we performed immunohistochemical and ultrastructural analysis. In vitro experiments were performed to demonstrate the relationship among microcalcification, BOLCs development, and breast cancer occurrence. Ex vivo investigations demonstrated the significant increase of breast osteoblast-like cells in breast lesions with microcalcifications with respect to those without microcalcifications. RESULTS In vitro data displayed that in the presence of calcium oxalate and activated monocytes, breast cancer cells undergo epithelial to mesenchymal transition. Also, in this condition, cells acquired an osteoblast phenotype, thus producing hydroxyapatite. To further confirm in vitro data, we studied 15 benign lesions with microcalcification from patients that developed a malignant condition in the same breast quadrant. Immunohistochemical analysis showed macrophages' polarization in benign lesions with calcium oxalate. CONCLUSIONS Altogether, our data shed new light about the role of microcalcifications in breast cancer occurrence and progression.
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7.
Macrophage: A Key Therapeutic Target in Atherosclerosis?
Taghizadeh, E, Taheri, F, Renani, PG, Reiner, Ž, Navashenaq, JG, Sahebkar, A
Current pharmaceutical design. 2019;(29):3165-3174
Abstract
BACKGROUND Atherosclerosis is a chronic inflammatory disease and a leading cause of coronary artery disease, peripheral vascular disease and stroke. Lipid-laden macrophages are derived from circulating monocytes and form fatty streaks as the first step of atherogenesis. METHODS An electronic search in major databases was performed to review new therapeutic opportunities for influencing the inflammatory component of atherosclerosis based on monocytes/macrophages targeting. RESULTS In the past two decades, macrophages have been recognized as the main players in atherogenesis but also in its thrombotic complications. There is a growing interest in immunometabolism and recent studies on metabolism of macrophages have created new therapeutic options to treat atherosclerosis. Targeting recruitment, polarization, cytokine profile extracellular matrix remodeling, cholesterol metabolism, oxidative stress, inflammatory activity and non-coding RNAs of monocyte/macrophage have been proposed as potential therapeutic approaches against atherosclerosis. CONCLUSION Monocytes/macrophages have a crucial role in progression and pathogenesis of atherosclerosis. Therefore, targeting monocyte/macrophage therapy in order to achieve anti-inflammatory effects might be a good option for prevention of atherosclerosis.
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8.
Immunologic cellular characteristics of the tumour microenvironment of hepatocellular carcinoma drive patient outcomes.
Atanasov, G, Dino, K, Schierle, K, Dietel, C, Aust, G, Pratschke, J, Seehofer, D, Schmelzle, M, Hau, HM
World journal of surgical oncology. 2019;(1):97
Abstract
BACKGROUND Anti-tumour immune competence has an impact in hepatocarcinogenesis and success of anti-cancer therapies. Tumour-infiltrating lymphocytes (TILs) and monocytes/macrophages (TAMs) are proposed to have significance in cancer. However, there is only limited data concerning their impact on patient outcome and survival in hepatocellular carcinoma (HCC). METHODS Frequencies of CD68+, CD163+ M2-polarized TAMs and TILs were measured in de novo HCC tumours in non-cirrhosis (n = 58) using immunohistology and correlated to patients' clinicopathological characteristics and survival rates. RESULTS Patients with tumours marked by appearance of TILs and CD68+ TAMs showed an improved 1-, 3- and 5-year recurrence-free survival (all p ≤ 0.05). CD68+ TAMs were associated with reduced incidence of recurrent and multifocal disease. Conversely, CD163+ TAMs were associated with multifocal HCC and lymphangiosis carcinomatosa (all p ≤ 0.05). CONCLUSIONS TILs and CD68+ TAMs are associated with multiple tumour characteristics and patient survival in HCC. However, there is only scarce data about the biology underlying their mechanistic involvement in human tumour progression. Thus, experimental data on functional links might help develop novel immunologic checkpoint inhibitor targets for liver cancer.
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9.
Human skeletal muscle macrophages increase following cycle training and are associated with adaptations that may facilitate growth.
Walton, RG, Kosmac, K, Mula, J, Fry, CS, Peck, BD, Groshong, JS, Finlin, BS, Zhu, B, Kern, PA, Peterson, CA
Scientific reports. 2019;(1):969
Abstract
Skeletal muscle macrophages participate in repair and regeneration following injury. However, their role in physiological adaptations to exercise is unexplored. We determined whether endurance exercise training (EET) alters macrophage content and characteristics in response to resistance exercise (RE), and whether macrophages are associated with other exercise adaptations. Subjects provided vastus lateralis biopsies before and after one bout of RE, after 12 weeks of EET (cycling), and after a final bout of RE. M2 macrophages (CD11b+/CD206+) did not increase with RE, but increased in response to EET (P < 0.01). Increases in M2 macrophages were positively correlated with fiber hypertrophy (r = 0.49) and satellite cells (r = 0.47). M2c macrophages (CD206+/CD163+) also increased following EET (P < 0.001), and were associated with fiber hypertrophy (r = 0.64). Gene expression was quantified using NanoString. Following EET, the change in M2 macrophages was positively associated with changes in HGF, IGF1, and extracellular matrix genes. EET decreased expression of IL6 (P < 0.05), C/EBPβ (P < 0.01), and MuRF (P < 0.05), and increased expression of IL-4 (P < 0.01), TNFα (P < 0.01) and the TWEAK receptor FN14 (P < 0.05). The change in FN14 gene expression was inversely associated with changes in C/EBPβ (r = -0.58) and MuRF (r = -0.46) following EET. In cultured human myotubes, siRNA inhibition of FN14 increased expression of C/EBPβ (P < 0.05) and MuRF (P < 0.05). Our data suggest that macrophages contribute to the muscle response to EET, potentially including modulation of TWEAK-FN14 signaling.
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10.
Assessing the reliability of gene expression measurements in very-low-numbers of human monocyte-derived macrophages.
Geiß, C, Alanis-Lobato, G, Andrade-Navarro, M, Régnier-Vigouroux, A
Scientific reports. 2019;(1):17908
Abstract
Tumor-derived primary cells are essential for in vitro and in vivo studies of tumor biology. The scarcity of this cellular material limits the feasibility of experiments or analyses and hence hinders basic and clinical research progress. We set out to determine the minimum number of cells that can be analyzed with standard laboratory equipment and that leads to reliable results, unbiased by cell number. A proof-of-principle study was conducted with primary human monocyte-derived macrophages, seeded in decreasing number and constant cell density. Gene expression of cells stimulated to acquire opposite inflammatory states was analyzed by quantitative PCR. Statistical analysis indicated the lack of significant difference in the expression profile of cells cultured at the highest (100,000 cells) and lowest numbers (3,610 cells) tested. Gene Ontology, pathway enrichment and network analysis confirmed the reliability of the data obtained with the lowest cell number. This statistical and computational analysis of gene expression profiles indicates that low cell number analysis is as dependable and informative as the analysis of a larger cell number. Our work demonstrates that it is possible to employ samples with a scarce number of cells in experimental studies and encourages the application of this approach on other cell types.